1. Field of the Invention
This invention relates to a novel amine compound or a salt thereof having excellent gonadotropin releasing hormone (GnRH) receptor antagonizing activity, a process for producing it, and a pharmaceutical composition containing it.
GnRH, which is a decapeptide consisting of 10 amino acids, is produced in the hypothalamus. It is known that GnRH regulates secretion of various hormones such as luteinizing hormone and follicle stimulating hormone through receptors which may be present in the anterior pituitary to thereby play a multi-pronged physiological role including induction of ovulation. Therefore, an antagonist or an agonist that is specific and selective for these receptors would modulate secretion of the anterior pituitary hormones. Therefore, such an antagonist or agonist can be expected to be useful for the prevention and treatment of anterior pituitary hormone-dependent diseases.
Since 1971 when GnRH was first discovered, a large number of its analogs have been synthesized in hopes of exploiting their agonistic or antagonistic activity. For example, leuprolerin acetate is a compound known to have a higher affinity for GnRH receptors than native GnRH and is less liable to be metabolized than the latter.
It is known that, when administered repeatedly, leuprolerin acetate, which is 20 to 50-fold as active as native GnRH, causes a receptor down-regulation to suppress the release and production of gonadotropin in the pituitary gland and in the testis, for it decreases the response to gonadotropin so that its testosterone producing capacity is diminished to the castrated level. It is known that, as a consequence, the drug displays antitumoral effects in hormone-dependent neoplastic diseases such as cancer of the prostate. In fact, leuprolerin acetate is clinically in broad use as a therapeutic drug for prostatic cancer and endometriosis, among other diseases.
However, these GnRH agonists are peptides which are poorly absorbed after oral administration and, hence, restricted in compatible dosage form. Moreover, there are cases in which they transiently manifest agonistic activity after the beginning of use and before the expected efficacy begins to appear, thus causing elevation of serum steroid hormone levels and transitory exacerbation of ostealgia.
Against this background, a great deal of research synthesis of GnRH antagonists which would show therapeutic efficacy and yet be free from the above-mentioned adverse effects has been eagerly undertaken.
2. Related Background Art
Today, as compounds having GnRH receptor antagonizing activity, a large number of cyclic hexapeptide derivatives (JP-A-61-191698) and bicyclic peptide derivatives [J. Med. Chem., 36, 3265-3273, 1993], all conceived from the steric structure of GnRH, have been designed and are known. However, since they all are peptides, these compounds still have the drawbacks of poor absorption after oral administration and poor in vivo stability.
Meanwhile, synthesis of non-peptide compounds having GnRH receptor antagonizing activity has also been attempted. By way of illustration, a benzazepine compound of the formula: ##STR2## [wherein R.sup.1 represents the amino function of an amine of the formula --NR.sup.3 R.sup.4, 4-morpholino, ##STR3## R.sup.2 represents hydrogen, alkoxy, alkyl, trifluoromethyl, halogen, nitro, hydroxyl, or dialkylamino; R.sup.3 and R.sup.4 independently represent hydrogen, alkyl, or alkyl substituted by hydroxyl, halogen or alkoxy; m is equal to 0 or 1; n is equal to 0, 1 or 2; R.sup.5 represents hydroxyl, alkyl, halogen, carboxyl, alkoxycarbonyl, or alkyl substituted by hydroxyl, halogen, alkoxy or phenyl; R.sup.6 represents hydrogen, alkyl, carboxyl, alkoxycarbonyl, or phenyl; and R.sup.7 represents hydrogen, alkyl, alkoxycarbonyl, or alkyl substituted by hydroxyl, halogen, alkoxy, phenoxy or alkoxycarbonyl] is reported in JP-A-62-116514. A compound of the formula: ##STR4## which has LHRH (luteinizing hormone-releasing hormone) antagonizing activity is reported in Journal of Medicinal Chemistry, 32, 2036-2038, 1989.
Meanwhile, it is described in JP-A-4-253970 corresponding to U.S. Pat. No. 5,393,959 that a compound of the formula: ##STR5## [wherein R.sub.1, R.sub.2 and R.sub.3 each represents hydrogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, CF.sub.3, or methylenedioxy; R.sub.4 represents hydrogen or C.sub.1-4 alkyl; A represents a bond or C.sub.1-6 alkylene or alkylidene; B is C.sub.1-6 alkylene or alkylidene when Y is a bond, or B is C.sub.2-6 alkylene when Y is O, S or NR.sup.5 ; X represents CH or N; R.sub.5 represents hydrogen or C.sub.1-4 alkyl] has intracellular calcium antagonizing activity and can be used as a therapeutic drug for angina pectoris and myocardial infarction.
Furthermore, Journal of Medicinal Chemistry, 34, 12-19 (1991) mentions that a compound of the formula: ##STR6## [wherein Ar.sup.1 and Ar.sup.2 each represents H, phenyl, or 2-, 3- or 4-pyridyl; Am represents 2,6-dimethyl-1-piperidinyl, 1-piperidinyl, or 2,5-dimethyl-1-pyrrolidinyl; n is equal to 1-4; X represents OH, H, cyano, aminomethyl, acetolaminomethyl or carbamoyl] has antiarrhythmic activity. Archives of International Pharmacodynamics, 107, 194-201, 1956 describes that a compound of the formula: ##STR7## [wherein R represents --CONH.sub.2, --NH.sub.2, --NHCOCH.sub.3, --NHCOC.sub.6 H.sub.5, --CH.sub.2 NH.sub.2, --CH.sub.2 NHCOCH.sub.3, --CH.sub.2 NHCOC.sub.6 H.sub.5 or --CN; NAA' represents N(CH.sub.3).sub.2, N(C.sub.2 H.sub.5).sub.2, N(i--C.sub.3 H.sub.7).sub.2, NC.sub.4 H.sub.8, NC.sub.5 H.sub.10 or NC.sub.4 H.sub.8 O] has parasympathomimetic activity.
JP-A-62-123164 mentions that a compound of the formula: ##STR8## [wherein X and Y, which may be the same or different, are selected from the class consisting of phenyl groups which may respectively be substituted by 1 or 2 substituents selected from among halogen, CF.sub.3, OH and C.sub.1-4 alkoxy; R.sup.1 and R.sup.2 are the same or different and each is selected from the class consisting of lower alkyl groups of 1-4 carbon atoms, or R.sup.1 and R.sup.2, taken together with the nitrogen atom, form a saturated 5- or 6-membered ring; R.sup.3 and R.sup.4 are selected from among hydrogen, lower alkyl or alkenyl of 1-6 carbon atoms, cyclopentyl and cyclohexyl; n is equal to 0 or 1] has antitumoral activity.
However, a non-peptide compound having sufficiently high GnRH receptor antagonizing activity for use as a medicine has not been discovered. Therefore, an aromatic amine derivative structurally different from the above-mentioned known compounds and having GnRH receptor antagonizing activity with a high clinical potential and safety has been awaited in earnest.